Benzothiophenyl benzothiophenylalkyl-N-terminal amino hydroxy β-amino acid derivatives

ABSTRACT

Non-peptidyl compounds characterized generally as benzothiophenyl/benzothiophenylalkyl-N-terminal amino hydroxy β-amino acid derivatives are useful as renin inhibitors for treatment of hypertension. Compounds of particular interest are of the formula ##STR1## wherein R 1  is selected from ##STR2## wherein each of Y and Z is independently selected from hydrido, chloro, fluoro, methoxy and dimethylamino; wherein X is sulfur atom; wherein n is a number selected from zero through four, inclusive; wherein each of R 2  and R 4  is independently selected from hydrido and methyl; wherein R 3  is methyl or ethyl; wherein R 5  is cyclohexylmethyl; wherein R 6  is hydroxy; and wherein R 7  is isobutyl or ethyl; or a pharmaceutically-acceptable salt thereof.

This is a divisional of application Ser. No. 07/445,257 filed Dec. 4,1989 now abandoned.

FIELD OF THE INVENTION

Renin-inhibiting compounds are known for control of hypertension. Ofparticular interest herein are non-peptidyl compounds useful as renininhibiting agents.

BACKGROUND OF THE INVENTION

Renin is a proteolytic enzyme produced and secreted into the bloodstreamby the juxtaglomerular cells of the kidney. In the bloodstream, renincleaves a peptide bond in the serum protein angiotensinogen to produce adecapeptide known as angiotensin I. A second enzyme known as angiotensinconverting enzyme, cleaves angiotensin I to produce the octapeptideknown as angiotensin II. Angiotensin II is a potent pressor agentresponsible for vasoconstriction and elevation of cardiovascularpressure. Attempts have been made to control hypertension by blockingthe action of renin or by blocking the formation of angiotensin II inthe body with inhibitors of angiotensin I converting enzyme.

Classes of compounds published as inhibitors of the action of renin onangiotensinogen include renin antibodies, pepstatin and its analogs,phospholipids, angiotensinogen analogs, pro-renin related analogs andpeptide aldehydes.

A peptide isolated from actinomyces has been reported as an inhibitor ofaspartyl proteases such as pepsin, cathepsin D and renin [Umezawa et al,in J. Antibiot. (Tokyo), 23, 259-262 (1970 )]. This peptide, known aspepstatin, was found to reduce blood pressure in vivo after theinjection of hog renin into nephrectomized rats [Gross et al, Science,175, 656 (1971 )]. Pepstatin has the disadvantages of low solubility andof inhibiting acid proteases in addition to renin. Modified pepstatinshave been synthesized in an attempt to increase the specificity forhuman renin over other physiologically important enzymes. While somedegree of specificity has been achieved, this approach has led to ratherhigh molecular weight hepta- and octapeptides [Boger et al, Nature, 303,81 (1983 )]; high molecular weight peptides are generally consideredundesirable as drugs because gastrointestinal absorption is impaired andplasma stability is compromised.

Short peptide aldehydes have been reported as renin inhibitors Kokubu etal. Biochim. Biophys. Res. Commun., 118, 929 (1984 ); Castro et al. FEBSLett., 167, 273 (1984 )]. Such compounds have a reactive C-terminalaldehyde group and would likely be unstable in vivo.

Other peptidyl compounds have been described as renin inhibitors. EPAppl. #128,762, published 18 December 1984, describes dipeptide andtripeptide glycol-containing compounds as renin inhibitors [also seeHanson et al. Biochim. Biophys. Res. Commun., 132, 155-161 (1985 ), 146,959-963 (1987 )]. EP Appl. #181,110, published 14 May 1986, describesdipeptide histidine derivatives as renin inhibitors. EP Appl. #189,203,published 30 July 1986, describes alkylnaphthyl-methylpropionyl-histidylaminohydroxy alkanoates as renin inhibitors. EP Appl. #216,539,published 1 April 1987, describes alkylnaphthylmethylpropionyl aminoacylaminoalkanoate compounds as renin inhibitors orally administered fortreatment of renin-associated hypertension. EP Appl. #229,667 published22 July 1987 describes acyl a-aminoacyl aminodiol compounds having apiperazinylcarbonyl or an alkylaminoalkylcarbonyl terminal group at theN-amino acid terminus, such as 2(S)-{[(1-piperazinyl)-carbonyl]-oxy]-3-phenylpropionyl}-Phe-His amide of2 (S)-amino-1-cyclohexyl-3 (R),4 (S)-dihydroxy-6-methylheptane. PCTApplication No. WO 87/04349 published 30 July 1987 describesaminocarbonyl aminoacyl hydroxyether derivatives having analkylamino-containing terminal substituent and which are described ashaving renin-inhibiting activity for use in treating hypertension. EPAppl. #300,189 published 25 January 1989 describes amino acid monohydricderivatives having an alkylamino-alkylamino N-terminus which arementioned o as useful in treating hypertension. EP Appl. #266,950published 5 November 1988 describes heterocycliccarbonyl amino acidderivatives which are mentioned as having renin-inhibiting activity foruse in treating hypertension.

DESCRIPTION OF THE INVENTION

Heterocyclic acyl aminodiol β-amino acid derivatives having utility asrenin inhibitors for treatment of hypertension in mammals constitute afamily of compounds of general Formula I: ##STR3## wherein R₁ isselected from aryl, aralkyl, heteroaryl and heteroaralkyl; wherein eachof R₂ and R₄ is independently selected from hydrido and lower alkyl;wherein R₃ is selected from hydrido, alkyl, benzyl, cycloalkyl,cycloalkylalkyl, alkoxyalkyl, alkylthioalkyl and imidazolemethyl;wherein R₅ is selected from cycloalkyl, phenyl, lower alkyl,cycloalkylalkyl and phenylalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino, dialkylamino, lower alkyl andcycloalkyl; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may be taken together to form a carbocyclic orheterocyclic ring consisting of from 3 to about 8 ring members, whichheterocyclic ring contains a hetero ring atom selected from oxygen atom,sulfur atom and NH; wherein each of R₈ and R₉ is independently selectedfrom hydrido, alkyl, phenylalkyl, cycloalkyl, heterocyclicalkyl andphenyl; wherein R₈ and R₉ may be taken together to form a carbocyclic orheterocyclic ring consisting of from three to about eight ring members,which heterocyclic ring contains a hetero ring atom selected from oxygenatom, sulfur atom and >NH; and wherein any of the foregoing R₁ throughR₉ substituents having a substitutable position may be substituted withone or more groups selected from alkyl, alkoxy, halo, haloalkyl,alkenyl, alkynyl and cyano; or a pharmaceutically-acceptable saltthereof.

A preferred family of compounds consists of those compounds of Formula Iwherein R₁ is selected from aryl and aralkyl groups represented by##STR4## and wherein R₁ may be further selected from heteroaryl andheteroaralkyl represented by wherein X is selected from O, S, alkylaminoand NH; wherein each of Y and Z is independently selected from loweralkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino,aryl, sulfhydryl and thioalkyl; wherein Q is selected from O and S;wherein each of T and A is independently selected from N and CH; whereinn is a number selected from zero through five, inclusive; wherein eachof R₂ and R₄ is independently selected from hydrido and lower alkyl;wherein R₃ is selected from hydrido, alkyl, alkoxyalkyl, alkylthioalkyland imidazolemethyl; H wherein R₅ is selected from substituted orunsubstituted lower alkyl, cycloalkylalkyl and phenylalkyl; wherein R₆is selected from hydrido, hydroxy, alkoxy, amino, alkylamino anddialkylamino; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may be taken together to form a carbocyclic orheterocyclic ring consisting of from 3 to about 6 members, whichheterocyclic ring contains a hetero ring atom selected from oxygen atom,sulfur atom and NH; wherein each of R₈ and R₉ is independently selectedfrom hydrido, alkyl, phenylalkyl, cycloalkyl, heterocyclicalkyl andphenyl; wherein R₈ and R₉ may be taken together to form a carbocyclic orheterocyclic ring consisting of from three to about six members, whichheterocyclic ring contains a hetero ring atom selected from oxygen atom,sulfur atom and >NH; and wherein any of the H foregoing R¹ through R⁹substituents may be substituted with one or more groups selected fromalkyl, alkoxy, halo, haloalkyl, alkenyl, alkynyl and cyano; or apharmaceutically-acceptable salt thereof.

A further preferred family of compounds consists of those compounds ofFormula I wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from hydrido, methyl, ethyl,methoxymethyl, methylthiomethyl and imidazolemethyl; wherein R₅ isselected from benzyl, cyclohexylmethyl, isobutyl and n-butyl; wherein R₆is selected from hydrido, hydroxy, methoxy and dialkylamino; wherein R₇is selected from isobutyl, ethyl, propyl and benzyl; wherein R₆ and R₇may be taken together to form a carbocyclic or heterocyclic ringconsisting of from 3 to about 6 members, which heterocyclic ringcontains a hetero ring atom selected from oxygen atom, sulfur atomand >NH; wherein each of R₈ and R₉ is independently selected fromhydrido, methyl, isopropyl, isobutyl, benzyl and imidazolemethyl;wherein R₈ and R₉ may be taken together to form a ring consisting offrom three to about six members, which heterocyclic ring contains ahetero ring atom selected from oxygen atom, sulfur atom and >NH; whereinX is selected from alkylamino, NH, oxygen atom and sulfur atom; whereineach of Y and Z is independently selected from lower alkyl, hydroxy,halo, alkoxy, amino, alkylamino, dialkylamino, aryl, sulfhydryl andthioalkyl; wherein Q is oxygen atom; wherein each of T and A isindependently selected from N and CH; wherein n is a number selectedfrom zero through four.

A more preferred family of .compounds consists of those compounds ofFormula I wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from methyl and ethyl whereinR₅ is oyclohexylmethyl; wherein R₆ is hydroxy; wherein R₇ is selectedfrom isobutyl and ethyl; wherein each of R₈ and R₉ is independentlyselected from hydrido, methyl and isopropyl; wherein X is selected fromoxygen atom, methylamino >NH; wherein each of Y and Z is independentlyselected from Cl, F, methoxy and dimethylamino; wherein Q is oxygenatom; wherein each of T and A is independently selected from N and CH;wherein n is a number selected from zero through four.

The term "hydrido" denotes a single hydrogen atom (H) which may beattached, for example, to a carbon atom to form hydrocarbyl ormethylene, for example, or attached to an oxygen atom to form a hydroxylgroup. Where the term "alkyl" is used, either alone or within otherterms such as "haloalkyl". "aralkyl" and "hydroxyalkyl". the term"alkyl" embraces linear or branched radicals having one to about twentycarbon atoms Preferred alkyl radicals are "lower alkyl" radicals havingone to about ten carbon atoms. Examples of which include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, neopentyl, n-hexyl, 1-methylhexyl, n-heptyl, 2-ethylheptyl,n-octyl, 3-propyloctyl, n-nonyl, 4-butylnonyl, n-decyl and the like. Theterm "cycloalkyl". embraces radicals having three to ten carbon atoms,such as cyclopropyl and cyclobutyl. "Alkylcycloalkyl" means a cyclizedalkyl having from four to about nine ring carbon atoms being substitutedwith an alkyl group, preferably a lower alkyl group The term "haloalkyl"embraces radicals wherein any one or more of the carbon atoms issubstituted with one or more halo groups, preferably selected frombromo, chloro and fluoro. Specifically embraced by the term "haloalkyl"are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkylgroup, for example, may have either a bromo, a chloro, or a fluoro atomwithin the group. Dihaloalkyl and polyhaloalkyl groups may besubstituted with two or more of the same halo groups, or may have acombination of different halo groups. A dihaloalkyl group, for example,may have two bromo atoms, such as a dibromomethyl group, or two chloroatoms, such as a dichloromethyl group, or one bromo atom and one chloroatom, such as bromochloromethyl group. Examples of a polyhaloalkyl aretrifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and2,2,3,3-tetrafluoropropyl groups. The term "aryl" embraces aromaticradicals such as phenyl, biphenyl and naphthyl. The term "aralkyl"embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyland triphenylmethyl. The terms "benzyl" and "phenylmethyl" areinterchangeable. The term "alkoxy" embraces linear or branchedoxy-containing radicals having an alkyl portion of one to about tencarbon atoms, such as methoxy, ethoxy, isopropoxy and butoxy. The term"alkylthio" embraces radicals containing a linear or branched alkylgroup of one to about ten carbon atoms attached to a divalent sulfuratom, such as a methythio group. The terms "aryloxy" and "arylthio"denote, respectively, aryl groups having an oxygen or sulfur atomthrough which the radical is attached to a nucleus, examples of whichare phenoxy and phenylthio. The terms "sulfinyl" and "sulfonyl". whetherused alone or linked to other terms, denote respectively, divalentradicals >SO and >SO₂. The term "acyl" whether used alone, or within aterm such as acyloxy, denotes a radical provided by the residueremaining after removal of hydroxy from an organic acid, examples ofsuch radical being lower alkanoyl, such as acetyl, and benzoyl. The term"alkenyl" embraces linear or branched radicals having two to abouttwenty carbon atoms, preferably three to about ten carbon atoms, andcontaining at least one carbon-carbon double bond. The term "alkynyl"embraces linear or branched radicals having two to about twenty carbonatoms, preferably two to about ten carbon atoms, and containing at leastone carbon-carbon triple bond. The terms "cycloalkenyl" and"cycloalkynyl" embrace cyclic radicals having three to about ten ringcarbon atoms including, respectively, one or more double or triple bondsinvolving adjacent ring carbons. The terms "alkoxy" and "alkoxyalkyl"embrace linear or branched oxy-containing radicals each having alkylportions of one to about ten carbon atoms, such as methoxy group. The"alkoxy" or "alkoxyalkyl" radicals may be further substituted with oneor more halo atoms, such as fluoro, chloro or bromo, to providehaloalkoxy or haloalkoxyalkyl groups. The terms "heteroaryl". "aromaticheterocyclic group" and "fully-unsaturated heterocyclic group" embracearomatic ring systems containing one or two hetero ring atoms selectedfrom oxygen, nitrogen and sulfur in a ring system having five to aboutten ring members; such ring system could be monocyclic, bicyclic, orfused ring system. The term "heteroaralkyl" embraces heteroaryl groupsattached to the nucleus of Formula I through an alkyl group. The term"heterocyclic" embraces groups which may be saturated or partiallyunsaturated having three to eight ring members and which heterocyclicring contains a hetero atom selected from oxygen atom, sulfur atom andNH, examples of which are thienyl, furanyl, pyridinyl and pyrimidyl. Theterm "heterocyclicalkyl" embraces heterocyclic groups attached to thenucleus of Formula I through an alkyl group.

Within this class of compounds of the invention are the pharmaceuticallyacceptable salts of the compounds of Formula I, including acid additionsalts and base addition salts. The term "pharmaceutically-acceptablesalts" embraces "pharmacologically-acceptable salts" commonly used toform alkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of which areformic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic,tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic,aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic,phenylacetic, mandelic, embonic (pamoic), methansulfonic,ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic,toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic,algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid.Suitable pharmaceutically-acceptable base addition salts of compounds ofFormula I include metallic salts made from calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made fromN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound of Formula I by reacting, for example, the appropriate acid orbase with the compound of Formula I.

Based upon the foregoing, the meanings of the following terms should bereadily discernible, namely, "cycloalkyl". "cycloalkylalkyl"."phenylalkyl" and "alkoxy".

Compounds of Formula I have been found to inhibit renin and thus limitthe production of angiotensin I which, in turn, limits the production ofangiotensin II in mammals. Angiotensin II is a potent vasoconstrictorand participates in the formation of aldosterone which regulates sodiumand water balance in mammals. Thus, compounds of Formula I aretherapeutically useful in methods for treating hypertension byadministering to a hypertensive patient a therapeutically-effectiveamount of a compound of Formula I. The phrase "hypertensive patient"means, in this context, a mammalian subject suffering from the effectsof hypertension or susceptible to a hypertensive condition if nottreated to prevent or control such hypertension.

These compounds can be formulated into pharmaceutically-acceptabledosage forms by any of a number of well-known carriers or diluents. Thecompounds can be formulated using pharmaceutically-acceptable acidaddition salts which are pharmacologically-acceptable and which can beused in a suitable hydrated form. The formulated compounds can beadministered in oral dosage forms such as tablets, capsules, pills,powders, or granules. The compounds can also be administeredintramuscularly, using forms known to the pharmaceutical art. Ingeneral, the preferred form of administration is oral. A therapeuticallyeffective but non-toxic quantity of the compound is employed intreatment of high blood pressure in mammals. The dosage regimen forpreventing or treating hypertension with the compounds of Formula I isselected upon consideration of a variety of factors, including the type,age, weight, sex, and medical condition of the patient, the severity ofthe hypertension, the route of administration, and the particularcompound employed. Dosages of active compounds are ordinarily in therange from about 0.5 to about 100 mg/kg (active compound-to-bodyweight), and preferably from about 1.0 to about 20 mg/kg given orally orby injection.

Compounds of Formula I are also useful as diagnostic agents foridentification of hypertension due to renin excess.

Compounds of Formula I can be administered as prodrugs. Preferably,esterification of one or more of the hydroxyl groups of the compounds ofFormula I is accomplished with amino acids to make aminoesters,succinates to makes succinic acid esters, alkanoic acids to makecarboxylic acid esters such as valerates, or phosphates to makephosphoric acid esters. Aminoesters and valerates of the Formula Icompounds are more preferred.

Procedures for preparation of compounds of Formula I are set forth inthe following "General Synthetic Scheme" and in the descriptions of thesynthesis of specific compounds described in Examples 1-26 which followthereafter

The following examples are provided to illustrate the present inventionand are not intended to limit the scope thereof. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethese compounds. All temperatures expressed are in degrees Centigrade.Within the foregoing synthetic description and examples which follow,abbreviations have meanings as indicated below:

Boc=t-butyloxycarbonyl

i-Bu=isobutyl

Leu=leucine

Ac=acyl

Me=methyl

TFA=trifluoroacetic acid

THF=tetrahydrofuran

im=imidazole

AMBA=alpha-methyl-β-analine (also known as 2-R-methyl-3-aminopropionicacid)

Procedures for preparation of compounds of Formula I are set forth inthe following "General Synthetic Scheme" and in the descriptions of thesynthesis of specific compounds described in Examples 1-26 which followthereafter. The synthesis of renin inhibitory compounds of Formula I maybe summarized as follows: A suitably protected β-amino acid, preferablyprotected with a t-butyloxycarbonyl group for nitrogen, is coupled to asuitably protected aminodiol using a published procedure [F. M. F. Chenet al, J. Org. Chem., 48, 2939 (1983 )]. This conjugate is then treatedwith trifluoroacetic acid (or other appropriate agent) to remove the Bocgroup, and this resulting material is neutralized and coupled usingMethods A, B, C or D (described below) to form heterocyclic orhomocyclic carboxylic acid derivatives to produce the renin inhibitorsof this invention. The substituents R¹ through R⁷ represent groups asmentioned above in the general description of compounds within FormulaI. ##STR5##

EXAMPLE 1 N-Boc-α-(R)-methyl-β-alanineamide of (2 S,3 R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

To a solution of N-Boc-α-(R,S)-methyl-β-alanine (137 mg, 0.67 mmol) inmethylene chloride (4 mL) at -10 ° C. was added N-methylpiperidine (61mg, 0.61 mmol) followed by isobutylchloroformate (75 mg, 0.55 mmol).After stirring for 5 min, a solution of (2 S,3 R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (101 mg, 0.41mmol) in methylene chloride (2 mL) was added. The resulting solution wasstirred for 3 hours at -10 ° C., followed by 2 hours at room temperatureat which time a white solid was isolated by filtration (60 mg, 34%yield): Rf=0.3 (5% MeOH/methylene chloride, silica gel); mp 197°-200°C.; 1H NMR (CDC13 ): consistent with proposed structure. Anal. calcd forC₂₃ H₄₄ N₂ O₅ +0.25 H₂ O: C, 63.77; H, 10.35; N, 6.46. Found: C, 63.84;H, 10.50; N, 6.45.

EXAMPLE 2 α-(R)-Methyl-β-alanineamide of (2 S,3 R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound of Example 1 (53 mg, 0.12 mmol) was stirred with amixture of trifluoroacetic acid and methanol (9:1, 5 mL). The resultingsolution was allowed to stand at room temperature for 20 minutes, thenthe solvent was evaporated. The resulting oil was stirred for 2 hourswith aqueous potassium carbonate (5%, 10 mL). This mixture was thenextracted with ethyl acetate which was dried, filtered and evaporated togive the title compound (40 mg, 100%): Rf: 0.10 (5% MeOH/methylenechloride, silica gel). This material was used without furtherpurification.

EXAMPLE 3 N-Methyl-N-Boc-α-(R)-methyl-β-alanine

To a solution of N-Boc-α-(R,S)-methyl-β-alanine (1.33 g, 6.5 mmol) inTHF (80 ml)was added pentane washed sodium hydride(1.2 g, 60% in oildispersion) followed by methyl iodide (2 ml, exess). The reactionmixture was stirred overnight and then poured into an iced solution ofcitric acid (0.5N). The aqueous THF solution was extracted into ethylacetate. Then the required acid was back extracted between ethylacetate, sodium hydrogen carbonate and potassium hydrogen sulphatesolutions. The organic extracts were dried (MgSO₄) and evaporated toafford the title compound. (1.00 g, 71%), Anal: C₁₀ H₁₉ NO₄.0.3H₂ O,Calc: C, 53.94; H, 8.87; N, 6.29. Found, C, 54.02; H, 8.56; N, 6.63.

EXAMPLE 4 N-Methyl-N-Boc-α-(R)-methyl-β-alanineamide of (2 S,3 R, 4S)-2-amino-1-cyclohexyl -3,4-dihydroxy-6-methylheptane

To a solution of N-Methyl-N-Boc-α-(R)-methyl-β-alanine (900 mg, 0.67mmol) in methylene chloride (10 mL) at -10° C. was addedN-methyl-piperidine (500 μl, 4.15 mmol) followed byisobutylchloroformate (450 mg, 3.3 mmol). After stirring for 5 min, asolution of (2 S,3 R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (655 mg, 2.7 mmol)in methylene chloride (4 mL) was added. The resulting solution wasstirred for 5 hours at -10 ° C. The solvent was evaporated in vacuo toafford an oily residue which was partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic layer was separated and dried(MgSO₄). After evaporation the crude residue was dissolved in methanol(4 mL) to which potassium hydroxide solution (1 mL, 1M) was added. Thereaction mixture was stirred for 30 min, evaporated to dryness and theresidue extracted into ethyl acetate. The organic extracts were washedwith water, citric acid (0.5M) and saturated sodium bicarbonate solutionand dried over MgSO₄. Evaporation of the solvent gave a yellow residuewhich was recrystallized from diethyl ether to afford the titlecompound. (850 mg, 71% yield), Anal: C₂₄ H₄₆ N₂ O₅, Calc, C, 65.12; H,10.47; N, 6.33; Found, C, 65.10; H,10.37; N, 6.43.

EXAMPLE 5 N-Methyl-α-(R)-methyl-β-alanineamide of (2 S,3 R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane.

The title compound of Example 4 (820 mg, 1.86 mmol) was stirred with amixture of trifluoroacetic acid and methanol (9:1, 5 mL). The resultingsolution was allowed to stand at room temperature for 20 minutes, thenthe solvent was evaporated. The resulting oil was stirred for 2 hourswith aqueous potassium carbonate (5%, 10 mL). This mixture was thenextracted with ethyl acetate which was dried, filtered evaporated andprecipitated from diethyl ethyl to afford the title compound. (580 mg,92%). Anal: C , Calc C, 64.59; H,11.18; N, 7.93; Found, C, 64.59; H,10.50; N, 7.61.

EXAMPLE 6 ##STR6## N-[3-[1S,1R*-(cyclohexylmethyl)-2 S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]benzenebutanamide

To a stirred solution of phenylbutyric acid (60 mg, 0.183 mmol) inmethylene chloride (2 mL) in an ice/salt bath was addedN-methylpiperidine (0.08 mL, 2 eq) followed by isobutylchloroformate (40mg, 1.6 eq). After 5 min, the title compound of Example 2 (60 mg, 0.183mmol) in methylene chloride/methanol [1 ml/0.1 ml) was added and thereaction mixture was stirred at 0 ° C. for about 15 hours. The solventwas evaporated in vacuo to afford an oily residue which was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organiclayer was separated and dried (MgSO₄). After evaporation the cruderesidue was dissolve in methanol (4 mL) to which potassium hydroxidesolution (1 mL,1 M) was added. The reaction mixture was stirred for 30min, evaporated to dryness and the residue extracted into ethyl acetate.The organic extracts were washed with water, citric acid (0.5 M) andsaturated sodium bicarbonate solution and dried over MgSO₄. Evaporationof the solvent gave a yellow residue which was re-crystallized fromdiethyl ether to afford the title compound. (38 mg, 44% yield), Anal:C₂₈ H₄₆ N₂ O₄.1.8 H₂ O, Calc, C, 66.32; H, 9.86; N, 5.52. Found, C,66.32; H, 9.18; N, 5.57.

EXAMPLE 7 (METHOD B) ##STR7##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-2-carboxamide

To a stirred solution of the title compound of Example 2 (150 mg, 0.46mmol) in methylene chloride/methanol (5 ml/0.2 ml) was addedtriethylamine (0.2 ml, excess) followed by indole-2-oyl chloride (160mg, 2 eq) and a catalytic amount of 4-dimethylaminopyridine. Thereaction mixture was stirred at 0° C. for 15 hours. The solvent wasevaporated in vacuo to afford an oily residue which was partitionedbetween ethyl acetate and saturated sodium bicarbonate. The organiclayer was separated and dried (MgSO₄). After evaporation the cruderesidue was dissolved in methanol (4 mL) to which potassium hydroxidesolution (1 mL, 1M) was added. The reaction mixture was stirred for 30min, evaporated to dryness and the residue extracted into ethyl acetate.The organic extracts were washed with water, citric acid (0.5M) andsaturated sodium bicarbonate solution and dried over MgSO₄. Evaporationof the solvent gave a yellow residue which was recrystallized fromdiethyl ether to afford the title compound. (85 mg, 40% yield), Anal:C₂₇ H₄₁ N₃ O₄, Calc, C, 68.72; H, 8.76; N, 8.91; Found: C, 68.62; H;8.63; N, 8.86.

EXAMPLE 8 (METHOD C) ##STR8## N-3-[[1S,1R*-(cyclohexylmethyl)-2 S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]benzofuran-2-carboxamide

To a stirred solution of the title compound of Example 2 (40 mg, 0.122mmol) in methylene chloride/pyridine (1 ml/1 ml) at room temperaturewere added benzofuran-2-carboxylic acid anhydride (74 mg, 2 eq) and acatalytic amount of 4-dimethylaminopyridine. The reaction mixture wasstirred for about 15 hours. The solvent was evaporated in vacuo toafford an oily residue which was partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic layer was separated and dried(MgSO₄). After evaporation the crude residue was dissolved in methanol(4 mL) to which potassium hydroxide solution (1 mL, 1 M) was added. Thereaction mixture was stirred for 30 min, evaporated to dryness and theresidue extracted into ethyl acetate. The organic extracts were washedwith water, citric acid (0.5M) and saturated sodium bicarbonate solutionand dried over MgSO₄. Evaporation of the solvent gave a yellow residuewhich was recrystallized from diethyl ether to afford the titlecompound. (30 mg, 52% yield), Anal: C.sub. 27 H₄₀ N₂ O₅. 1.3 H₂ O, Calc:C, 65.35; H, 8.66; N, 5.65. Found, C, 65.32; H, 8.43; N, 5.55.

EXAMPLE 9 (METHOD D) ##STR9## N-3-[[1S,1R*-(cyclohexylmethyl)-2 S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]1H-indole-2-acetamide

To a stirred solution of the title compound of Example 2 (60 mg, 0.183mmol) a catalytic amount of 4-dimethylaminopyridine and indole-2-aceticacid (32 mg, leq) in DMF (2 ml) was addeddimethylaminopropyl-3-ethylcarbodiimide (35 mg, leq) at 0 ° C. Thereaction mixture was stirred at room temperature for about 15 hours. Thesolvent was evaporated in vacuo to afford an oily residue which waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic layer was separated and dried (MgSO₄). After evaporation thecrude residue was dissolved in methanol (4 mL) to which potassiumhydroxide solution (1 mL, 1 M) was added. The reaction mixture wasstirred for 30 min, evaporated to dryness and the residue extracted intoethyl acetate. The organic extracts were washed with water, citric acid(0.5M) and saturated sodium bicarbonate solution and dried over MgSO₄.Evaporation of the solvent gave a yellow residue which wasrecrystallized from diethyl ether to afford the title compound (65 mg,72% yield), Anal: C₂₈ H₄₃ N₃ O₄, Calc, C, 69.25; H, 8.92; N, 8.65;Found, C, 69.17; H, 9.13; N, 8.56.

EXAMPLE 10 (METHOD D) ##STR10## N-3-[[1S,1R*-(cyclohexylmethyl)-2 S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-N-methylbenzenebutanamide

The title compound of Example 5 was coupled to 4-phenylbutyric acidusing Method A. (56% yield), Anal: C₂₉ H₄₈ N₂ O₄.0.2 H₂ O, Calc, C,70.75; H, 9.91; N, 5.69; Found, C, 70.83; H, 9.72; N, 5.77.

EXAMPLE 11 ##STR11## N-[3-[[1S,1R*-(cyclohexylmethyl)-2 S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]cyclohexanebutanamide

The title compound of example 2 was coupled to 4-cyclohexylbutyric acidusing Method A (58% yield). Anal: C₂₈ H₅₂ N₂ O₄, Calc, C, 69.96; H,10.90; N, 5.83; Found, C, 69.76; H, 10.95; N, 5.79.

EXAMPLE 12 ##STR12##N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-N-methylcyclohexanebutanamide

The title compound of Example 5 was coupled to 4-cyclohexylbutyric acidusing Method A. (70% yield) Anal: C₂₉ H₅₄ N₂ O₄.0.2 H₂ O, Calc, C,69.89; H, 11.00; N, 5.62; Found, C, 69.97; H. 11.00; N, 5.50.

EXAMPLE 13 ##STR13##N-[3-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-methoxybenzenepropanamide

The title compound of Example 2 was coupled to3-(4-methoxyphenylpropionic acid using Method A. (68% yield), Anal: C₂₈H₄₆ N₂ O₅, Calc, C, 68.54; H, 9.45; N, 5.71; Found, C, 68.24,; H, 9 58;N, 5.75.

EXAMPLE 14 ##STR14##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropy]-2-quinaldylamide

27 mg (0.16 mmoles) of quinaldic acid was coupled to 30 mg (0.09 mmoles)of title compound of Example 2 using coupling Method A. Yield: 96%. 200MHz NMR consistent with structure. C: cal'd, 69.54; found, 68.21. H:cal'd, 8.54; found, 8.84. N: cal'd, 8.69; found, 8.23. 95.34% pure byHPLC.

EXAMPLE 15 ##STR15##N-[3-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-2-quinoxalinecarboxamide

86 mg (0.494 mmoles) of 2-quinoxalinecarboxylic acid was coupled to 101mg (0.307 mmoles) of title compound of Example 2 using coupling MethodA. Yield: 92%. 200 MHz NMR consistent with structure. C: cal'd, 66.92;found, 67.17. H: cal'd, 8.32; found, 8.38. N: cal'd, 11.56; found,11.36.

EXAMPLE 16 ##STR16##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-nalidixylamide

117 mg (0.504 mmoles) of nalidixic acid was coupled to 104 mg (0.317mmoles) of title compound of Example 2 using coupling Method A. Yield:115 mg. 200 MHz NMR consistent with structure. C: cal'd, 66 39; found,65.73. H: cal'd, 8.54; found, 8.48. N: cal'd, 10.32; found, 10.09.91.70% pure by HPLC.

EXAMPLE 17 ##STR17##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-(R,S)-α-methyl-hydrocinnamide

0.487g (2.97 mmoles) of α-methyl-hydrocinnamic acid was coupled to 0.609g (1.85 mmoles) of title compound of Example 2 using coupling Method A.Yield: 90 mg. 200 MHz NMR consistent with structure. C: cal'd, 70.85;found, 66.63. H: cal'd, 9.77; found, 9.81. N: cal'd, 5.90; found, 6.13.

EXAMPLE 18 ##STR18##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]N-methyl-1H-indole-2-carboxamide

The title compound of Example 5 was coupled to indole-2-carboxylic acidusing Method B. (50%) Anal: C₂₈ H₄₃ N₃ O₄.0.2H₂ O Calc: C, 68.14; H,8.94; N 8.5 g; Found: C, 68.68; H, 8.88; N, 8.97.

EXAMPLE 19 ##STR19##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]]amino-2S*-methyl-3-oxopropyl]-5-fluoro-1H-indole-3-carboxamide

The title compound of Example 2 was coupled to5-fluoroindole-2-carboxylic acid using Method A. yield), Anal: C₂₇ H₄₀N₃ O₄ F.1.0 H₂ O, Calc, C, 63.88; H, 8.34; N, 8.28; Found, C, 63.98; H,7.96; N:8.04.

EXAMPLE 20 ##STR20##N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-carboxamide

The title compound of Example 2 was coupled to indole-3-carboxylic acidusing Method B. (58% yield), Anal: C₂₇ H₄₁ N₃ O₄,Calc, C, 68.24; H,.8.78; N, 8.84; Found, C, 68.05; H, 8.26; N, 8.89.

EXAMPLE 21 ##STR21##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-acetamide

The title compound of Example 2 was coupled to indole-3-acetic acidusing Method B.(56% yield), Anal: C₂₈ H₄₃ N₃ O₄.0.7H2O, Calc, C, 67.49;H, 8.98; N, 8.43; Found, C, 67.63; H, 8.96; N, 8.26.

EXAMPLE 22 ##STR22##N-[3-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-1H-indole-3-propanamide

The title compound of Example 2 was coupled to indole-3-propionic acidusing method A. (81% yield), Anal: C₂₉ H₄₅ N₃ O₄, Calc, C, 69.71; H,9.08; N, 8.41; Found, C, 69.26; H, 9.13; N, 8.28.

EXAMPLE 23 ##STR23##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl[-7-chlorobenzofuran-2-carboxamide

The title compound of Example 2 was coupled to7-chlorobenzofuran-2-carboxylic acid using Method A. (38% yield), Anal:C₂₇ H₃₉ N₂ O₅ Cl, Calc,C:63.96, H:7.75, N:5.52, Found, C:64.24, H:8.36,N:5.64.

EXAMPLE 24 ##STR24##N-[3-[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-7-methoxybenzofuran-2-carboxamide

The title compound of Example 2 was coupled to7-methoxybenzofuran-2-carboxylic acid using Method A(40% yield). Anal:C₂₈ H₄₂ N₂ O₆,Calc, C, 66.91; H, 8.42; N, 5.57; Found, C, 66.45; H,8.34; N, 4.83.

EXAMPLE 25 ##STR25##N-3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-oxo-4H-1-benzopyran-3-carboxamide

The title compound of Example 2 was coupled to chromone-3-carboxylicacid using Method A: (54% yield), Anal: C₂₈ H₄₀ N₂ O₆, Calc, C, 67.18;H, 8.05; N, 5.60; Found, C, 66.82; H, 8.08; N, 5.47.

EXAMPLE 26 ##STR26##N-[3-[[1S,1R*-(cyclohexylmethyl)-2S*,3R*-dihydroxy-5-methylhexyl]amino]-2S*-methyl-3-oxopropyl]-4-oxo-4H-1-benzopyran-2-carboxamide

AMBA-diol was coupled to chromone-2-carboxylic acid using Method A (40%yield). Anal: C₂₈ H₄₀ N₂ O₆. 0.8H₂ O, Calc, C, 65.30; H, 8.14; N, 5.44;Found, C, 65.35; H, 7.74; N, 5.41.

BIOLOGICAL EVALUATION

Compounds of Formula I were evaluated as inhibitors of human renin in anin vitro assay. This human renin inhibition test has been previouslydescribed in detail [Papaioannou et al., Clinical and ExperimentalHypertension, A7(9), 1243-1257 (1985)]. Human renin was obtained fromthe National Institute for Biologivcal Standards, London. An incubationmixture was prepared containing in a total volume of 0.25 mL 100 mMTris-acetate buffer at pH 7.4, 25×10⁻⁶ Goldblatt units of renin, 0.05 mLof plasma from human volunteers taking oral contraceptives, 6.0 mMsodium EDTA, 2.4 mM phenylmethyl sulfonyl fluoride, 1.5 mM8-hydroxyquinoline, 0.4 mg/mL BSA, and 0.024 mq/mL neomycin sulfate.This mixture was incubated for two hours at 37° C. in the presence orabsence of renin inhibitors. The produced angiotensin I was determinedby radioimmunoassay (New England Nuclear kit). Test compounds to beassayed were dissolved in DMSO and diluted with 100 mM Tris-acetatebuffer at pH 7.4 Containing 0.5% BSA to the appropriate concentration.The final concentration of organic solvent in the reaction mixture wasless than 1%. Contro incubations at 37° C. were used to correct foreffects of organic solvent on renin activity.

    ______________________________________                                        In Vitro Inhibition Data                                                      Example #      IC.sub.50 Human Renin (nM)                                     ______________________________________                                         6             125                                                             7             26                                                             10             115                                                            11             180                                                            12             23% inhibition @ 10.sup.-6 M                                   13             30% inhibition @ 5 × 10.sup.-7 M                         16             450                                                            20             27% inhibition @ 10.sup.-5 M                                   21             30% inhibition @ 10.sup.-6 M                                   22             430                                                            23             1800                                                           24             3000                                                           25             1100                                                           26             520                                                            ______________________________________                                    

Administration of compounds within Formula I to humans can be by anytechnique capable of introducing the compounds into the bloodstream of ahuman patient, including oral administration, and by intravenous,intramuscular and subcutaneous injections.

Compounds indicated for prophylactic therapy will preferably beadministered in a daily dose generally in a range from about 0.1 mg toabout 100 mg per kilogram of body weight per day. A more preferreddosage will be a range from about 1 mg to about 100 mg per kilogram ofbody weight. Most preferred is a dosage in a range from about 1 to about50 mg per kilogram of body weight per day. A suitable dose can beadministered, in multiple sub-doses per day. These sub-doses may beadministered in unit dosage forms. Typically, a dose or sub-dose maycontain from about 1 mg to about 100 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 50 mg of active compound per unit dosage form. Most preferred is adosage form containing from about 3 mg to about 25 mg of active compoundper unit dose.

The active compound is usually administered in apharmaceutically-acceptable formulation, although in some acute-caresituations a compound of Formula I may be administered alone. Suchformulations may comprise the active compound together with one or morepharmaceutically-acceptable carriers or diluents. Other therapeuticagents may also be present in the formulation. Apharmaceutically-acceptable carrier or diluent provides an appropriatevehicle for delivery of the active compound without introducingundesirable side effects. Delivery of the active compound in suchformulations may be by various routes including oral, nasal, topical,buccal and sublingual, or by parenteral administration such assubcutaneous, intramuscular, intravenous and intradermal routes.

Formulations for oral administration may be in the form of capsulescontaining the active compound dispersed in a binder such as gelatin orhydroxypropylmethyl cellulose, together with one or more of a lubricant,preservative, surface-active or dispersing agent. Such capsules ortablets may contain controlled-release formulation as may be provided ina dispersion of active compound in hydroxypropylmethyl cellulose.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. Compound of the formula ##STR27## wherein R₁ isselected from heteroaryl and heteroaralkyl groups represented by##STR28## wherein each of Y and Z is independently selected fromhydrido, lower alkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino,dialkylamino, aryl, sulfhydryl and thioalkyl; wherein X is sulfur atom;wherein n is a number selected from zero through five, inclusive;wherein each of R₂ and R₄ is independently selected from hydrido, alkyl,benzyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl and alkylthioalkyl;wherein R₅ is selected from cycloalkyl, phenyl, lower alkyl,cycloalkylalkyl and phenylalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino, dialkylamino, lower alkyl andcycloalkyl; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may be further taken together to form a carbocyclicring consisting of from three to about eight ring members; and whereinany of the foregoing R₁ through R₇ substituents having a substitutableposition may be substituted with one or more groups selected from alkyl,alkoxy, halo, haloalkyl, alkenyl, alkynyl and cyano; or apharmaceutically-acceptable salt thereof.
 2. Compound of claim 1 whereineach of Y and Z is independently selected from hydrido, lower alkyl,hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino, aryl,sulfhydryl and thioalkyl; wherein X is sulfur atom; wherein n is anumber selected from zero through five, inclusive; wherein each of R₂and R₄ is independently selected from hydrido and lower alkyl; whereinR₃ is selected from hydrido, alkyl, alkoxyalkyl and alkylthioalkyl;wherein R₅ is selected from substituted or unsubstituted lower alkyl,cycloalkylalkyl and phenylalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino and dialkylamino; wherein R₇ isselected from hydrido, alkyl, haloalkyl, cycloalkylalkyl,alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl; wherein R₆ and R₇may further be taken together to form a carbocyclic ring consisting offrom three to about six members; and wherein any of the foregoing R₁through R₇ substituents having a substitutable position may besubstituted with one or more groups selected from alkyl, alkoxy, halo,haloalkyl, alkenyl, alkynyl and cyano; or a pharmaceutically-acceptablesalt thereof.
 3. Compound of claim 2 wherein each of Y and Z isindependently selected from hydrido, lower alkyl, hydroxy, halo, alkoxy,amino, alkylamino, dialkylamino, aryl, sulfhydryl and thioalkyl; whereinX is sulfur atom; wherein n is a number selected from zero through four,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from hydrido, methyl, ethyl,methoxymethyl and methylthiomethyl; wherein R₅ is selected from benzyl,cyclohexylmethyl, isobutyl and n-butyl; wherein R₆ is selected fromhydrido, hyroxy, methoxy and dialkylamino; wherein R₇ is selected fromisobutyl, ethyl, propyl and benzyl; and wherein R₆ and R₇ may be takentogether to form a carbocyclic ring consisting of from three to aboutsix members; or a pharmaceutically-acceptable salt thereof.
 4. Compoundof claim 3 wherein each of Y and Z is independently selected fromhydrido, chloro, fluoro, methoxy and dimethylamino; wherein X is sulfuratom; wherein n is a number selected from zero through four, inclusive;wherein each of R₂ and R₄ is independently selected from hydrido andmethyl; wherein R₃ is selected from methyl and ethyl; wherein R₅ iscycloexylmethyl; wherein R₆ is hydroxy; and wherein R₇ is selected fromisobutyl and ethyl; or a pharmaceutically-acceptable salt thereof.
 5. Apharmaceutical composition comprising a therapeutically-effective amountof a renin-inhibiting compound and a pharmaceutically-acceptable carrieror diluent, said renin-inhibiting compound selected from a family ofcompounds of the formula ##STR29## wherein R₁ is selected fromheteroaryl and heteroaralkyl groups represented by ##STR30## whereineach of Y and Z is independently selected from hydrido, lower alkyl,hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino, aryl,sulfhydryl and thioalkyl; wherein X is sulfur atom; wherein n is anumber selected from zero through five, inclusive; wherein each of R₂and R₄ is independently selected from hydrido and lower alkyl; whereinR₃ is selected from hydrido, alkyl, benzyl, cycloalkyl, cycloalkylalkyl,alkoxyalkyl and alkylthioalkyl; wherein R₅ is selected from cycloalkyl,phenyl, lower alkyl, cycloalkylalkyl and phenylalkyl; wherein R₆ isselected from hydrido, hydroxy, alkoxy, amino, alkylamino, dialkylamino,lower alkyl and cycloalkyl; wherein R₇ is selected from hydrido, alkyl,haloalkyl, cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl andalkoxycarbonyl; wherein R₆ and R₇ may further be taken together to forma carbocyclic ring consisting of from three to about eight ring members;and wherein any of the foregoing R₁ through R₇ substituents having asubstitutable position may be substituted with one or more groupsselected from alkyl, alkoxy, halo, haloalkyl, alkenyl, alkynyl andcyano; or a pharmaceutically-acceptable salt thereof.
 6. The compositionof claim 5 wherein each of Y and Z is independently selected fromhydrido, lower alkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino,dialkylamino, aryl, sulfhydryl and thioalkyl; wherein X is sulfur atom;wherein n is a number selected from zero through five, inclusive;wherein each of R₂ and R₄ is independently selected from hydrido andlower alkyl; wherein R₃ is selected from hydrido, alkyl, alkoxyalkyl andalkylthioalkyl; wherein R₅ is selected from substituted or unsubstitutedlower alkyl, cycloalkylalkyl and phenylalkyl; wherein R₆ is selectedfrom hydrido, hydroxy, alkoxy, amino, alkylamino and dialkylamino;wherein R₇ is selected from hydrido, alkyl, haloalkyl, cycloalkylalkyl,alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl; wherein R₆ and R₇may further be taken together to form a carbocyclic ring consisting offrom three to about six members; and wherein any of the foregoing R₁through R₇ substituents having a substitutable position may besubstituted with one or more groups selected from alkyl, alkoxy, halo,haloalkyl, alkenyl, alkynyl and cyano; or a pharmaceutically-acceptablesalt thereof.
 7. The composition of claim 6 wherein each of Y and Z isindependently selected from hydrido, lower alkyl, hydroxy, halo, alkoxy,amino, alkylamino, dialkylamino, aryl, sulfhydryl and thioalkyl; whereinX is sulfur atom; wherein n is a number selected from zero through four,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from hydrido, methyl, ethyl,methoxymethyl and methylthiomethyl; wherein R₅ is selected from benzyl,cyclohexylmethyl, isobutyl and n-butyl; wherein R₆ is selected fromhydrido, hydroxy, methoxy and dialkylamino; wherein R₇ is selected fromisobutyl, ethyl, propyl and benzyl; and wherein R₆ and R₇ may be takentogether to form a carbocyclic ring consisting of from three to aboutsix members; or a pharmaceutically-acceptable salt thereof.
 8. Thecomposition of claim 7 wherein each of Y and Z is independently selectedfrom hydrido, chloro, fluoro, methoxy and dimethylamino; wherein X issulfur atom; wherein n is a number selected from zero through four,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from methyl and ethyl;wherein R₅ is cyclohexylmethyl; wherein R₆ is hydroxy; and wherein R₇ isselected from isobutyl and ethyl; or a pharmaceutically-acceptable saltthereof.
 9. A therapeutic method for treating hypertension, said methodcomprising administering to a hypertensive patient atherapeutically-effective amount of a compound of the formula ##STR31##wherein R₁ is selected from heteroaryl and heteroaralkyl groupsrepresented by ##STR32## wherein each of Y and Z is independentlyselected from hydrido, lower alkyl, hydroxy, halo, alkoxy, carboxy,amino, alkylamino, dialkylamino, aryl, sulfhydryl and thioalkyl; whereinX is sulfur atom; wherein n is a number selected from zero through five,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and lower alkyl; wherein R₃ is selected from hydrido, alkyl,benzyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl and alkylthioalkyl;wherein R₅ is selected from cycloalkyl, phenyl, lower alkyl,cycloalkylalkyl and phenylalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino, dialkylamino, lower alkyl andcycloalkyl; wherein R₇ is selected from hydrido, alkyl, haloalkyl,cycloalkylalkyl, alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl;wherein R₆ and R₇ may further be taken together to form a carbocyclicring consisting of from three to about eight ring members; and whereinany of the foregoing R₁ through R₇ substituents having a substitutableposition may be substituted with one or more groups selected from alkyl,alkoxy, halo, haloalkyl, alkenyl, alkynyl and cyano; or apharmaceutically-acceptable salt thereof.
 10. The method of claim 9wherein each of Y and Z is independently selected from hydrido, loweralkyl, hydroxy, halo, alkoxy, carboxy, amino, alkylamino, dialkylamino,aryl, sulfhydryl and thioalkyl; wherein X is sulfur atom; wherein n is anumber selected from zero through five, inclusive; wherein each of R₂and R₄ is independently selected from hydrido and lower alkyl; whereinR₃ is selected from hydrido, alkyl, alkoxyalkyl and alkylthioalkyl;wherein R₅ is selected from substituted or unsubstituted lower alkyl,cycloalkylalkyl and phenylalkyl; wherein R₆ is selected from hydrido,hydroxy, alkoxy, amino, alkylamino and dialkylamino; wherein R₇ isselected from hydrido, alkyl, haloalkyl, cycloalkylalkyl,alkylcycloalkyl, alkylcycloalkenyl and alkoxycarbonyl; wherein R₆ and R₇may further be taken together to form a carbocyclic ring consisting offrom three to about six members; and wherein any of the foregoing R₁through R₇ substituents having a substitutable position may besubstituted with one or more groups selected from alkyl, alkoxy, halo,haloalkyl, alkenyl, alkynyl and cyano; or a pharmaceutically-acceptablesalt thereof.
 11. The method of claim 10 wherein each of Y and Z isindependently selected from hydrido, lower alkyl, hydroxy, halo, alkoxy,amino, alkylamino, dialkylamino, aryl, sulfhydryl and thioalkyl; whereinX is sulfur atom; wherein n is a number selected from zero through four,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from hydrido, methyl, ethyl,methoxymethyl and methylthiomethyl; wherein R₅ is selected from benzyl,cyclohexylmethyl, isobutyl and n-butyl; wherein R₆ is selected fromhydrido, hydroxy, methoxy and dialkylamino; wherein R₇ is selected fromisobutyl, ethyl, propyl and benzyl; and wherein R₆ and R₇ may be takentogether to form a carbocyclic ring consisting of from three to aboutsix members; or a pharmaceutically-acceptable salt thereof.
 12. Themethod of claim 11 wherein each of Y and Z is independently selectedfrom hydrido, chloro, fluoro, methoxy and dimethylamino; wherein X issulfur atom; wherein n is a number selected from zero through four,inclusive; wherein each of R₂ and R₄ is independently selected fromhydrido and methyl; wherein R₃ is selected from methyl and ethyl;wherein R₅ is cyclohexylmethyl; wherein R₆ is hydroxy; and wherein R₇ isselected from isobutyl and ethyl; or a pharmaceutically-acceptable saltthereof.